The long term goal of this project is to identify and characterize the molecules produced in the central nervous system that support the survival, growth and differentiation of neurons and glia. Progress has been made in the study of neurotrophic factors by using cell culture systems. We have shown that transferrin is a survival factor for neurons. Transferrin is produced in the brain by oligodendrocytes and the choroid plexus. Since transferrin plays a major role in iron metabolism, it suggests an important function for oligodendrocytes in addition to myelination of axon tracts. We propose to study the mechanisms underlying the lack of myelin formation and transferrin gene expression in the myelin-deficient mutant rat. We will also use cell culture systems to study transcription factors regulating transferrin gene activity in various brain cell types. The cell cultures will be used to determine the identity of growth factors, hormones, and other brain-cell derived factors regulating transferrin expression. Several areas of the brain, oligodendrocytes and myelin contain higher levels of iron than the liver. Dramatic shifts in iron distribution and concentration are seen in human neurodegenerative diseases. The potential release of free iron in neurodegenerative diseases, such as demyelinating disorders, as well as in injury due to trauma, can lead to free radical formation. Little is known about how the brain responds to this challenge. Apotransferrin can act as an antioxidant; therefore, the regulation of transferrin gene expression is very important in the brain since it serves several functions during development, in the adult brain, in the pathogenesis of neurodegenerative disorders and in injury. We also propose to develop a transplant model to study the influence of the in vivo environment, both normal and abnormal, on the differentiation and function of the subpopulations of cells that arise from the oligodendrocyte-type II astrocyte progenitor cell. This project impacts on problems of nervous system development since iron deficiency affects nearly one million infants worldwide and transferrin is essential for neuronal survival and function. Information obtained from these studies will help lead to a better understanding of the factors necessary for normal development.